This application in response to the RFA for the Tumor Microenvironment Network (TMEN) will focus on[unreadable] mouse models of cancer initiation and progression, particularly in the breast and lung and involving both[unreadable] transplantable and autochthonous (i.e. spontaneous endogenous) tumors. The applicant group is[unreadable] multidisciplinary, involving investigators expert in mouse models, cancer cell biology, molecular imaging and[unreadable] proteomics. The individual subprojects will focus on specific components of the tumor microenvironment;[unreadable] cells, secreted factors and extracellular matrix (collectively termed stroma), as well as on the nature of the[unreadable] immune response to cancer.[unreadable] We will investigate the following topics:-[unreadable] 1. stromal influences on why and how tumor cells initially become invasive and metastatic as a[unreadable] consequence of stromal effects at the site of the primary tumor.[unreadable] 2. microenvironmental effects that can suppress or enhance the seeding, survival and growth of metastases[unreadable] at secondary sites.[unreadable] 3. the identity and origins of stromal cells (mesenchymal and hematopoietic) induced at, or recruited to, the[unreadable] site of a primary tumor, how they are recruited, and how they affect the progression of the tumor[unreadable] 4. the nature of immune surveillance of autochthonous tumors[unreadable] 5. the nature of different tumor extracellular matrices (ECMs) and interactions of both tumor and stromal[unreadable] cells with ECM[unreadable] 6. we will further develop novel imaging probes and methods to detect, track and ablate different subsets of[unreadable] stromal cells in mouse models of cancer.[unreadable] 7. we will use lentiviral-mediated RNA interference both to initiate autochthonous tumors and to manipulate[unreadable] the functions of both tumor and stromal cells.[unreadable] It is becoming increasingly recognized that tumor cells do not progress to malignancy in isolation - the[unreadable] microenvirnment of the tumor can either enhance or suppress tumor growth and progression. This program[unreadable] will provide new information and novel technological approaches to questions concerning the effects of the[unreadable] surrounding microenvironment in which tumors develop. It is expected that new insights from this research[unreadable] will offer novel approaches to intervene in the progression of tumors to malignancy.